This application focuses on the prevention of cerebral and myocardial injury during cardiac arrest and resuscitation. Our hypothesis is that a major mechanism of such injury is the nitric oxide-superoxide-peroxynitrite pathway. Our aim is to show that pharmacological modification of this pathway, using nitric oxide synthase inhibitors, both nonselective and neuronal selective, will ameliorate resuscitation injury and thereby enhance survival from cardiac arrest, and preserve post-arrest cerebral and cardiac function. We will test a series of specific hypotheses. We propose that nonselective NOS inhibitors, given during VF cardiac arrest-defibrillation-resuscitation sequences, enhance resumption of spontaneous circulation and improve post-arrest left ventricular performance. Conversely, nitric oxide donors given during arrest and resuscitation exacerbate cardiac resuscitation injury by increasing toxic peroxynitrite generation. We propose to demonstrate, in coronary microvessels and isolated vascular rings, a specific mechanism of cardiac resuscitation injury direct current shock-induced loss of normal endothelial-mediated coronary arterial vasodilation. We will show that NOS inhibitors protect against this mechanism. Finally, in survival experiments, we will show that selective neuronal nNOS inhibition preserves neurologic function 48 hours after cardiac arrest and resuscitation and minimizes histopathological neuronal damage, while nonselective NOS inhibition enhances cardiac performance at 48 hours after arrest. More effective treatment of resuscitation-induced cardiac and brain injury is imperative for improved survival of the estimated 300,000 US victims of cardiac arrest every year.